title: Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis.
abstract: BACKGROUND
  Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy.
  
  
  METHODS
  We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis.
  
  
  RESULTS
  Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P < 10(-5)) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ.
  
  
  CONCLUSIONS
  The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.
authors.affiliation: McGill International TB Centre and Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Cobat
authors.forename: Eileen G
authors.initials: EG
authors.lastname: Hoal
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Gallant
authors.forename: Leah
authors.initials: L
authors.lastname: Simkin
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Black
authors.forename: Kim
authors.initials: K
authors.lastname: Stanley
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jaïs
authors.forename: Ting-Heng
authors.initials: TH
authors.lastname: Yu
authors.forename: Anne
authors.initials: A
authors.lastname: Boland-Auge
authors.forename: Ghislain
authors.initials: G
authors.lastname: Grange
authors.forename: Christophe
authors.initials: C
authors.lastname: Delacourt
authors.forename: Paul
authors.initials: P
authors.lastname: van Helden
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001500:BCG Vaccine / Q000008:administration & dosage*; D016009:Chi-Square Distribution; D002648:Child; D002880:Chromosomes, Human, Pair 11; D019353:Endemic Diseases; D005190:Family; D058685:Genetic Pleiotropy; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage; D059425:Interferon-gamma Release Tests; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D015810:Linkage Disequilibrium; D009163:Mycobacterium bovis / Q000276:immunology*; D010641:Phenotype; D040641:Quantitative Trait Loci; D013019:South Africa / Q000453:epidemiology; D014376:Tuberculosis / Q000097:blood / Q000453:epidemiology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics* / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: TNF; multivariate linkage analysis; pleiotropic locus; tuberculosis